Effect of low dose acetylsalicylic acid and anticoagulant on clinical outcomes in COVID‐19, analytical cross‐sectional study

Abstract Background and aims The therapeutic strategy for the treatment of known sequelae of COVID‐19 has shifted from reactive to preventative. In this study, we aim to evaluate the effects of acetylsalicylic acid (ASA), and anticoagulants on COVID‐19 related morbidity and mortality. Methods This record‐based analytical cross‐sectional study targeted 539 COVID‐19 patients in a single United States medical center between March and December 2020. Through a random stratified sample, we recruited outpatient (n = 206) and inpatient (n = 333) cases from three management protocols, including standard care (SC) (n = 399), low‐dose ASA only (ASA) (n = 112), and anticoagulation only (AC) (n = 28). Collected data included demographics, comorbidities, and clinical outcomes. The primary outcome measure was inpatient admission. Exploratory secondary outcome measures included length of stay, 30‐day readmission rates, medical intensive care unit (MICU) admission, need for mechanical ventilation, the occurrence of acute respiratory distress syndrome (ARDS), bleeding events, clotting events, and mortality. The collected data were coded and analyzed using standard tests. Results Age, mean number of comorbidities, and all individual comorbidities except for asthma, and malignancy were significantly lower in the SC compared to ASA and AC. After adjusting for age and comorbidity via binary logistic regression models, no statistical differences were found between groups for the studied outcomes. When compared to the SC group, ASA had lower 30‐day readmission rates (odds ration [OR] 0.81 95% confidence interval [CI] 0.35–1.88, p = 0.63), MICU admission (OR 0.63 95% CI 0.34–1.17, p = 0.32), ARDS (OR 0.71 95% CI 0.33–1.52, p = 0.38), and death (OR 0.85 95% CI 0.36–1.99, p = 0.71). Conclusion Low‐dose ASA has a nonsignificant but potentially protective role in reducing the risk of COVID‐19 related morbidity and mortality. Our data suggests a trend toward reduced 30‐day readmission rates, ARDS, MICU admissions, need for mechanical ventilation, and mortality compared to the standard management protocol. Further randomized control trials are needed to establish causal effects.

Conclusion: Low-dose ASA has a nonsignificant but potentially protective role in reducing the risk of COVID-19 related morbidity and mortality. Our data suggests a trend toward reduced 30-day readmission rates, ARDS, MICU admissions, need for mechanical ventilation, and mortality compared to the standard management protocol. Further randomized control trials are needed to establish causal effects.  1 The majority of COVID-19 cases are mild to moderate, but 14% of cases are severe with up to 5% of cases in critical condition experiencing respiratory failure, shock, or multisystem dysfunction. 2 In early 2020, hospitalizations due to COVID-19 accounted for 14% of reported cases in the United States, with 2% admitted to the intensive care unit (ICU). 2 The vast majority of COVID-19 cases do not require hospitalization, and those patients are sent home to quarantine without further medical intervention. As a result, less information regarding complications arising from outpatient COVID-19 cases is documented.
Current guidelines for managing outpatients with COVID-19 include mostly supportive care. Of note, there is no current guideline recommending low-dose acetylsalicylic acid (ASA) for prehospital COVID-19 patient. 3 ASA has been used in medicine for over a century and is known for its pleiotropic effects. 4 Specifically, ASA is known to reduce platelet activation by inhibiting the formation of thromboxane A2 but has also been found to have direct antiviral properties. 4,5 Severe COVID-19 infection is predominantly a multisystem inflammatory process resulting in disease pathogenesis manifesting as ARDS, endothelial dysfunction, and coagulopathy. [6][7][8] With ASA's anti-inflammatory, antiplatelet aggregation, and anticoagulation properties, it is often prescribed as a secondary preventative measure in cardiovascular disease. 8,9 Given this, it has been suggested that ASA and other antiplatelet agents may play a preventative role in reducing coagulopathy complications that have been shown to arise in 25%-42% of COVID-19 patients. 10,11 Lowdose ASA may also improve overall clinical outcomes in COVID-19 patients by reducing ICU admission, time spent on mechanical ventilation, and hospital mortality. 8 A recent study showed that patients with COVID-19 who received low-dose ASA were associated with a lower incidence of requiring mechanical ventilation, ICU admission, and in-hospital mortality. 11 Other studies have shown that ASA helps reduce mortality in patients with COVID-19 who have taken ASA, but the evidence lacks high certainty. 6 However, some studies suggest no association between the use of low-dose ASA and mortality in COVID-19 patients. 7 Given the wide effects of low-dose ASA and previous studies suggesting conflicting results of ASA administration in COVID-19 patients, we compared the outcome of low-dose ASA use in primary prevention of hospitalization and improving overall clinical outcomes in patients with COVID-19.

| MATERIALS AND METHODS
This record-based analytical cross-sectional study collected a stratified random sample of 539 patients from a total of 2714 available confirmed COVID-19 patients at a single upstate New York, USA medical center between March 1, 2020, and December 1, 2020.
Patient information was collected from both the inpatient and outpatient settings.
The criteria for inclusion into the study included all confirmed COVID-19 cases that were identified by a positive result of real-time polymerase-chain-reaction, aged 18-89 years old, and exclusion criteria included: current pregnancy, current clopidogrel use, current incarceration, a prior history of thromboembolism or hereditary hypercoagulable disorder, and surgery or hospitalization for reasons other than COVID-19-related illness during or 14 days before the indexing period.

| Sample size
The sample size was estimated according to the following equation: (n = Z2) P (1 − P)/d2. From the total number of 2714 potentially relevant cases, Based on the reported cases at the study setting between March 1, 2020, and December 1, 2020, and based on the prevalence of our primary outcome (inpatient admission) in the United States, hospitalizations due to COVID-19 accounted for 14% of reported cases, 2 at a 95% confidence level and 80% power of the study, as a stratified sample to represent the three management protocols and to increase the probability of detecting secondary outcomes like ICU admission, which was reported to be 2% in the United States. 2 The calculated sample size was 539. Patients who met the selection criteria were randomly recruited and stratified per proportions and distributed into the three management protocols per care setting into: standard care (SC) (n = 399) (74.0%), ASA only (ASA) (n = 112) (20.8%), and anticoagulation only (AC) (n = 28) (5.2%) with the associated percentage of total patients being outpatient (n = 206) (37.8%) and inpatient (n = 333) (62.2%). Patients who reached inpatient care through hospital admission were not counted in the outpatient group.
Groups were defined as: • Patients in the ASA group take 81-160 mg of ASA orally every day. Due to hospital standards, patients in this group were also taking prophylactic dosing of anticoagulants as in the SC group.
Patients taking therapeutic anticoagulants were excluded from this group.
• Patients taking any anticoagulant agent as a home medication at therapeutic dosing: patients taking any anticoagulant agents alone at therapeutic dosing as a home medication. Anticoagulants include novel oral anticoagulants, warfarin, and heparin products.
Patients taking low-dose (81-162 mg PO daily) or taking any anticoagulation agents during the indexing period were excluded from this group.
All groups were treated with the same basic management protocol based on guidelines by Upstate University Hospital.

| Study data
Information obtained from patient records included demographic data, comorbidities, clinical outcome data (primary and secondary as listed below in study objectives), and mortality. Medication history was used to identify patients taking ASA and other anticoagulants.

| Study objectives
The objective of this study was to study the effects of ASA and anticoagulants on COVID-19-related outcomes. The primary outcome measure in this study was inpatient hospital admission.
Additionally, exploratory methods were used to evaluate secondary outcomes including length of hospital stay, 30-day readmission rates, medical intensive care unit (MICU) admission, need for mechanical ventilation, the occurrence of ARDS, bleeding events, clotting events, and mortality.

| Statistical analysis
The collected data were coded and analyzed using Statistical Package Software Statistics (SPSS) version 26.0 (IBM Corp.). Qualitative data summarization was prepared using frequency (f) and percentage (%); χ 2 was used for the analysis of these variable. Mean, standard deviation (SD), two-sided independent t-test, and two-sided analysis of variance (ANOVA) test were used for quantitative, normally distributed data summarization, and analysis. While median, Interquartile range, and two-sided Kruskal-Wallis tests were used for summarization, and analysis of nonparametric quantitative variables.
p value is the probability of finding the observed or more extreme results when the null hypothesis is true and considered significant when p < 0.05; the 95% confidence interval (CI) will contain the true parameter value. 95% of the time, a study has to be repeated many times using different samples.
Before using logistic regression, all assumptions of logistic regression were satisfied; mortality is an outcome. Multicollinearity in regression analysis occurs when two or more predictor variables are highly correlated to each other, for example, age, number of comorbidities, and variance inflation factor (VIF) values were rounded to 1.1, which means no correlation between a given predictor variable and any other predictor variables in the model ( Table 1).
The following tests were used to predict COVID-19 outcomes, including primary outcomes (inpatient admissions) and exploratory secondary outcomes (30-day readmission rates, the occurrence of ARDS, ICU admission, and death) through the following tests: Hosmer and Lemeshhow test, χ 2 , degree of freedom (df), Omnibus MALIK ET AL. | 3 of 11 test model χ 2 , Cox and Snell R 2 , Nagelkerke R 2 , and overall percentage.
Quantitatively, before separation into inpatient and outpatient arms, all studied outcomes showed a statistically significant difference between groups (p < 0.05) including inpatient admission, bleeding events, and death with the exception of clotting events. There were 333 patients identified for the COVID-19 inpatient portion of this study. These were distributed into the following: SC n = 223 (66.9%), ASA n = 87 (26.1%), and AC n = 23 (6.9%). There was a statistically significant difference (p < 0.05) between the SC group and other groups regarding age, mean number of comorbidities, and comorbidities except for asthma, and malignancy. Again, the SC group was significantly younger with fewer comorbidities than the other groups. All studied primary and secondary outcomes did not show statistically significant differences except for mean length of stay (LOS), which was significantly longer in the AC when compared to SC and ASA (12 vs. 7 vs. 6 days, p = 0.00) ( Table 3).
Through multivariate analysis, the odds of inpatient admission were found to be equivalent among all groups when adjusted for age and comorbidity (

| DISCUSSION
This record-based analytical cross-sectional study reported that the use of low-dose ASA has no statistical significance but a potential protective role in the management of COVID-19 as it was associated with a lower risk of 30-day hospital readmission, ICU admission, need T A B L E 2 The demographic and clinical characteristics of the studied groups. for mechanical ventilation, ARDS, and mortality when compared to the SC. It showed that AC increases the risk of all studied outcomes except the risk of ICU admission, which was decreased, compared to the SC. However, multicenter randomized control trials are needed to assess the causality effects of these therapies.
In this study, the randomly selected patients were distributed into the three management protocols, in which the majority of COVID-19 cases were managed with the SC protocol (74%), and the remaining were managed with prophylactic AC and ASA (20.8%), and therapeutic anticoagulation (5.2%). Due to this distribution, more than 80% of COVID-19 cases had mild symptoms, with critical cases being less than 10%. 12 There was a statistically significant difference The main limitations of our study are that it was a single-center, record-based, retrospective study, and that the AC group was small in number. The study design is a descriptive cross-sectional study. It is classified by the proportion of the use of each, which describes the prevalence of use of each (what's going on at Upstate University).
The main strengths of our study were that the relatively large sample size was collected over the long duration of the pandemic, T A B L E 5 Binary logistic regression analysis for predicting secondary outcomes (30-day readmission rates, ICU admission, ARDS occurrence, and death among inpatient cases). from March until December, and the many outcomes were studied in detail. Every case fulfilling the selection criteria has an equal chance of being recruited into the sample (so it is a random sample) to find the association and risk assessment.

| CONCLUSIONS
Low-dose ASA is a promising, effective, protective medication in potentially improving the outcomes in COVID-19 cases, through reducing mortality, and morbidity (hospital readmission rates, the occurrence of ARDS, and ICU admission) but not statistically significant due to the higher risk patients in these groups. further prospective research is still needed.